Clevidipine butyrate is a dihydropyridine calcium channel blocker, currently indicated for the reduction of blood pressure, when oral therapy is not feasible or not desirable. Its chemical name is butyroxymethyl 4-(2,3-dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate and its chemical structure is depicted below:

It is commercialized under the brand name of Cleviprex®, as a racemic mixture, in which each enantiomer has antihypertensive activity. Cleviprex® is an emulsion, suitable for intravenous applications.
Clevidipine butyrate was first described in WO 95/12578 (U.S. Pat. No. 5,856,346), as a very useful short-acting steerable antihypertensive drug, for intravenous administration.
WO 95/12578 discloses a method for preparing clevidipine butyrate from 1,4-dihydro-2,6-dimethyl-4-(2′,3′-dichlorophenyl)-5-carboxymethyl-3-pyridinecarboxylic acid and chloromethyl butyrate. This route has several drawbacks. Firstly, the purification of the final product is carried out by chromatographic methods, which are generally expensive, environmentally unfriendly and time consuming, therefore not recommended for industrial application. A second negative aspect is the nature of the solvent used. WO 95/12578 teaches that the reaction must be carried out in DMF or acetonitrile, both polar aprotic solvents, therefore reducing significantly the number of industrially suitable solvents. For instance, acetonitrile, the solvent used in patent application WO 00/31035 (U.S. Pat. No. 6,350,877), has suffered a worldwide commercial shortage over the last few years. Moreover, DMF, a solvent considered as a possible carcinogen by the International Agency for Research on Cancer (IARC), has been linked to cancer in humans and to cause birth defects.
Additionally, the inventors have found that in order to achieve the purity requirements needed for an injectable formulation, the product as obtained in the WO 95/12578 would have to be purified further.
WO 00/31035 seeks to reduce some of the drawbacks associated with the process disclosed in the WO 95/12578. The improvement is related to the use of the sodium and potassium salt of the 4-(2′,3′-dichlorophenyl)-1,4-dihydro-5-methoxycarbonyl-2,6-dimethyl-3-pyridinecarboxylate, instead of the acid form previously described. The improved process is depicted below:

Although said process offers some improvements over the prior art, it still has some limitations. Similarly to WO 95/12578, chloromethyl butyrate is also used in the last reaction step. According to the material safety data sheet of chloromethyl butyrate, it is corrosive, flammable and it can cause eye burns, skin burns, gastrointestinal tract burns and chemical burns to the respiratory tract. Therefore, its use increases the production costs as it is necessary use special equipment and manufacturing facilities. The use of chloromethyl butyrate should be avoided in the last steps of synthetic processes, where the equipment is more expensive. The excess use of chloromethyl butyrate would lead to the generation of additional impurities similar in nature to the final product. It is well known in the art, that the more similar two compounds are, the more difficult the purification is. Consequently, clevidipine butyrate, directly obtained by the processes disclosed in WO 00/31035, would have to be further purified in order to be used in the manufacture of pharmaceutical compositions. This mandatory extra purification step is time consuming and difficult to be carried out on an industrial scale. In any case, this approach will lead to the formation of at least one equivalent of sodium chloride, which will have to be removed.
Equally to WO 95/12578, the last step to obtain clevidipine butyrate is limited to the use of a polar aprotic solvent reducing significantly the number of industrially suitable solvents. Since the last reaction step takes place in acetonitrile and being clevidipine butyrate soluble in said solvent, a solvent-exchange must be performed in order to isolate clevidipine butyrate in a solid form from the reaction media.
Moreover, the process disclosed in WO 95/12578 implies the use of the cyanide intermediate, cyanoethyl methyl 4-(2′,3′-dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate, to obtain the dihydropyridine carboxylate salt. As it is well known in the art, many cyanide-containing compounds are toxic, since they can readily release hydrogen cyanide (HCN) or cyanide ions. Both, HCN or the cyanide ions, are highly toxic to animals and human beings. The cyanide group is introduced as a protecting group. This means that the use of the cyanide intermediate leads to an increase of the number of manufacturing steps (protection followed by deprotection and purification) to prepare clevidipine butyrate. Although the yield disclosed for the last synthetic steps is relatively high, as a result of the increased number of manufacturing steps, the overall yield will not be that high when the overall synthesis (starting from the raw materials) is taken into consideration.
In accordance with health registration requirements of the U.S. and international health registration authorities, e.g. the FDA's Good Manufacturing Practices (“GMP”) requirements, when preparing pharmaceutical compositions containing clevidipine butyrate for administration to mammals, there is a need to produce crystalline forms, or polymorphs, of clevidipine butyrate as pure as possible. Especially important are those forms, which have constant physical properties. Although those differences disappear once the compound is dissolved, they can appreciably influence pharmaceutically relevant properties of the solid form, such as handling properties, dissolution rate and stability. Such properties can significantly influence the processing, shelf life, and commercial acceptance of a polymorph.